S-adenosyl-L-methionine (“SAMe”) is a naturally occurring compound that is present in tissues throughout the body. At the molecular level, SAMe is involved in various metabolic pathways, including transmethylation, transsulfuration and aminopropylation.

In the body, SAMe is synthesized from an amino acid, methionine, and a triphosphate nucleotide, ATP. SAMe has been tested in numerous clinical trials for the treatment of various ailments, including arthritis, liver disease and depression.
SAMe supplementation was initially considered impractical, due to the instability of the SAMe ion during manufacturing, shipping and storage. Eventually stable salts of SAMe were developed (such as SAMe tosylate disulfate, the butanedisulfonate salt of SAMe, the di-para-toluene sulfonate disulfate of SAMe, the tri-para-toluene sulfonic acid salt of SAMe and the like). These salts can be formulated using standard, known technologies used for non-parenteral administration including but not limited to tablets, capsules and pellets. Formulations such as these may also comprise a coating which can serve multiple purposes such as reducing stomach irritation, improving taste and ease of swallowing, as well as stabilizing the encapsulated SAMe from elements such as moisture. Stable salts of SAMe are described in, for example, U.S. Pat. Nos. 3,954,726 and 4,057,686, both of which are incorporated herein by reference in their entirety. Conventional SAMe API is supplied as a molecular entity comprising an ion along with several counter-ions. For example, SAMe ion plus a tosylate and 2 sulfonic acid counter-ions make up commercially available adenosylmethionine disulfate-p-toluenesulfonate (also referred to as SAMe tosylate disulfate). When referring to SAMe dosing, it is currently accepted in the art that the numerical dose (usually in milligrams) refers to the amount of SAMe ion which is administered. For example, reference to a “400 mg SAMe tablet” of the SAMe tosylate disulfate would include the 400 mg of SAMe ion, another 370 mg of the counter-ions, and 200-300 mg of additional excipient to make up a final tablet weight of 1.0-1.1 grams. Thus, for example, a 1600 mg oral dose of SAMe which is generally reported in the art would typically be a dose of four such 1.0-1.1 gram tablets taken at one time. Alternatively, the same 1600 mg dose of SAMe ion may also be accomplished by administration of other combinations of multiple tablets such as, sixteen 100 mg or eight 200 mg tablets of SAMe ion taken at a given time. Conventional oral dosage forms of SAMe are most commonly produced with about 400 mg of SAMe ion; above that, the larger dosage form becomes difficult for swallowing considering that even at 400 mg of SAMe ion the tablets are quite large at 1.0-1.1 grams.
Exogenous SAMe exposure may be measured by looking at multiple pharmacokinetic parameters, the most common being the Cmax, Tmax and AUC. After non-parenteral administration of SAMe, its concentration in the blood increases until it reaches a peak concentration, this measured in plasma is the Cmax, and the time taken to reach the Cmax is termed, Tmax. The area under the (plasma concentration) curve, or AUC, is another useful measurement and represents the drug exposure in the systemic circulation over a period of time.
A few studies examining these pharmacokinetic parameters in humans have been recorded for SAMe. The role of intravenous (IV) versus oral administration of SAMe has been investigated to a small extent as well as the effect of repeat dosing over time. Giulidori et al., report plasma drug levels and half-lives of SAMe after a single, IV administered dose (Giulidori, P. et al., (1984) Eur. J. Clin. Pharmacol. 27:119.) Another group looked at SAMe plasma levels after a single, orally administered dose (Stramentinoli, G. (1987) Am. J. Med. 83:35.) A recent study examines SAMe pharmacokinetic parameters after one-day and five-day doses of orally and IV administered SAMe tosylate disulfate (Yang, J. et al (2009) Clin. Therapeutics, 31 (2): 311.) The prior art indicates that the half-life of oral SAMe is short and that AUC values of oral formulations are low.
There exists a need in the art to generate non-parenteral SAMe formulations with improved pharmacokinetic profiles compared to conventional prior art SAMe dosage forms. For example, those which have increased Cmax and/or AUC values as well as those which are more potent and exhibit similar Cmax and AUC values at low doses of SAMe. High Cmax or AUC formulations may produce an increased biological response to SAMe supplementation and ‘high potency’ formulations would have the benefit of a lower pill count and potentially increased tolerability for desired Cmax and/or AUC values.